US5700775A - Method and treatment composition for decreasing patient time in catabolic state after traumatic injury - Google Patents
Method and treatment composition for decreasing patient time in catabolic state after traumatic injury Download PDFInfo
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- US5700775A US5700775A US08/410,353 US41035395A US5700775A US 5700775 A US5700775 A US 5700775A US 41035395 A US41035395 A US 41035395A US 5700775 A US5700775 A US 5700775A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
Definitions
- Growth hormone releasing hormone factor is a peptide of 44 amino acids. There are analogs containing 27 to 44 amino acids. It is one of a group of peptides secreted by the hypothalamus, and it normally stimulates pituitary growth hormone release of the several isoforms of growth hormone and their respective control mechanisms or "feedback loops". It is important in normal growth and development during childhood.
- growth hormone releasing factor initiates the cascade of endocrine hormone secretions, starting with the growth hormones, which serve to control the body's growth and maintenance functions. This can be referred to as the body's fundamental anabolic axis. It has been shown that, when deficient, this cascade or axis can be reactivated by growth hormone releasing factor in children with short stature for therapeutic purposes to increase growth velocity and also in the elderly or in adults generally with growth hormone deficiencies.
- GRF(1-44)-NH 2 may have some promise in the treatment of growth hormone deficiency (see Journal of Clinical Endocrinology and Metab. 59:1, 1984 and Journal of Clinical Endocrinology and Metab., 58:1043, 1984).
- GRF(1-44)-NH 2 has not been marketed or suggested for any specific clinical disease treatment. It has been suggested as likely to be useful for testing pituitary function by using doses to stimulate pituitary secretion of growth hormone. The theory being that in the event it does not so stimulate, one knows that the pituitary gland is not functioning properly.
- GRF(1-44)-NH 2 is administered intravenously by a single bolus injection, and blood levels of growth hormone are measured in serum specimens obtained at approximately half hour intervals for four hours. If growth hormone levels fail to rise, then the presumption is made that the pituitary gland is incapable of secreting growth hormone. This is a single dose for diagnostic purposes, not a periodic and regular treatment pattern.
- growth hormone releasing factor either alone or in combination with parathyroid hormone, is used for treatment of osteoporosis, especially postmenopausal osteoporosis.
- additional useful treatments include new pre and post surgical trauma treatment that provides significantly enhanced patient recovery.
- the "ebb phase” is dominated by rapid mobilization of carbohydrates and fat. Glucose is released from stores of glycogen in the liver, while free fatty acids and glycerol are mobilized from adipose tissue. This response has been considered to be mediated mainly by release of stress hormones in response to trauma. However, energy expenditure is low in relation to the large amount of fuels available during this early period after trauma. If death does not occur due to massive blood loss or injury of vital organs, the “ebb phase” merges into the flow or "catabolic” phase, normally within 12-24 hours after the injury. During the "flow phase", energy expenditure is elevated and accompanied by an increased breakdown of body tissues. The duration of this period is more variable, and depends primarily on the severity of the injury.
- hyperglycemia is the earliest reported change in carbohydrate metabolism following trauma.
- the degree of hyperglycemia found post-traumatically has been shown to be correlated to the severity of injury.
- the hyperglycemia is also accompanied by a reduction in metabolic clearance rate of glucose.
- the respiratory quotient is low, indicating an increased utilization of fat relative to that of carbohydrate.
- Hastening the change from catabolic to anabolic state and strengthening the anabolic effect of body repair mechanisms would be useful in nearly all traumatic injury cases, regardless of the cause of the traumatic injury, whether it be voluntary, such as during elective surgery, or physical trauma caused by accident.
- a primary objective of the present invention is to provide a method of treatment which hastens the change from catabolic to anabolic state after a human patient's traumatic injury.
- Another objective of the present invention is to provide a method of treatment for traumatic injuries which uses human growth hormone releasing factor or biologically acceptable analogs thereof either alone or in combination with other actives to synergistically hasten patient conversion from a catabolic state to an anabolic state.
- Another objective of the present invention is to provide a method of successfully administering GRF(1-44)-NH 2 or biologically acceptable analogs thereof, either alone or concurrently with other actives to reduce the traumatic injury risk to patients.
- An even further objective of the present invention is to provide an injectable administration composition, by intravenous, intramuscular, subcutaneous, or any sustained release method, which accomplishes each of the above objectives.
- this invention involves treatment by administering on a periodic and regular basis to patients who either have suffered traumatic injury, or are about to suffer traumatic injury during surgery, an effective amount of human growth hormone releasing factor or a biologically active analog of human growth hormone releasing factor.
- the administration preferably by injectable, occurs for a time period sufficient to hasten the patient's change from a catabolic to an anabolic state. The administration may continue throughout the recovery period of the patient.
- GRF(1-44)-NH 2 is an attractive molecule for treatment of trauma injury because the molecule is relatively small and simple, and therefore can be effective in systemic absorption. It is small enough to be absorbed across mucous membranes and reach the circulation intact in relatively high concentration. Since it is necessary to give the growth hormone releasing factor repeatedly over a period of time after injury, administration by injection is preferred. Administration by techniques such as intramuscular, subcutaneous or intravenous administration is best in initial stages after trauma. It is also conceivable that growth hormone releasing factor may be given orally by pill or capsule, nasal insufflation, or by rectal or vaginal suppository, but to date no such non-injection methods have yet been developed for commercial use.
- the time of administration of the human GRF(1-44)-NH 2 normally continues throughout the recovery period from the traumatic injury.
- the preferred administration is by injection.
- Dosage level for GRF will vary depending upon age, weight and size of the patient, but typically satisfactory results may be obtained when administered at levels within the range of 50 micrograms to 3,000 micrograms daily. If one knows that the patient is about to undergo traumatic injury such as by elective surgery, it is helpful to begin the administration just prior to surgery and continue it through the time of recovery, at least until the patient is clearly converted from the catabolic to the anabolic phase.
- the time between catabolic and anabolic phase for patients after traumatic injury can even be further hastened where response to growth hormone releasing factor is augmented by the conjunctive application of pyridostigmine or other agents for the suppression of samatostatin such as argenine, certain beta blockers, and other agents.
- This augmentation can be accomplished with the application of from 30 mg. to 60 mg. of oral pyridostigmine given at least 30 minutes prior to injection with GRF. It is believed that this works because pyridostigmine suppresses samatostatin.
- Samatostatin is a growth hormone releasing suppresser.
- the growth hormone response to GRF is therefore intensified in normals when pyridostigmine or other samatostatin suppressing agents are administered.
- growth hormone releasing factor in releasing the several growth hormones and activating the anabolic axis can be enhanced by the use of a class of small peptides, and analogs thereof, as well and chemical mimics of these peptides, generally referred to as growth hormone releasing peptides (see Growth Hormone II--Basic and Clinical Aspects, Springer/Verlag, 1994, Pg. 167). While the mechanisms are not understood, these peptides, and their analogs and chemical mimics, tend to cause the release of at least one species of growth hormone and to suppress the effect of samatostatin. Accordingly, this invention includes the use of these agents separately, or in combination with growth hormone releasing factor or its analogs, to effect the release of the growth hormones to accomplish the anabolic benefits herein sought.
- GRF GRF alone
- other agents such as androgenic sex steroids of which testosterone analogs are an example.
- a range dose of testosterone analogs would be from 5 mg. to 30 mg. per day.
- growth hormone releasing factor GRF(1-44)-NH 2 With respect to growth hormone releasing factor GRF(1-44)-NH 2 , it should be noted that biologically active analogs thereof may also be used. There are several analogs of GRF(1-44)-NH 2 which have biological activity, but are somewhat less potent. It is contemplated that those analogs which are biologically active may also be used in the treatment process of the invention. Generally, growth hormone releasing factor analogs in both the free acid and amide forms, containing from 1-27 to 1-44 may have activity.
- active analogs may be selected from the group consisting of GRF(1-44)-NH 2 , GRF(1-44)-OH, GRF(1-40)-OH, GRF(1-40)-NH 2 , GRF(1-32)-NH 2 , GRF(1-39)-NH 2 , GRF(1-40)-Phe-NH 2 , GRF(1-40)-Phe-OH, GRF(1-40)-Phe-Gin-NH 2 , GRF(1-29)-NH 2 , and GRF(1-27)-NH 2 .
- the following example is set forth to provide a sample protocol for administration of human GRF(1-44)-NH 2 or its biologically active analogs in conjunction with traumatic injury to convert from catabolic to anabolic state.
- a patient suffers multiple fractures and soft tissue injuries of the extremities and trunk (in an automobile accident). After admission to the hospital, the acute problems of airway obstruction and blood loss are controlled. Open reduction of fractures is performed as required and returned to intensive care unit for recovery after surgery. GRF injections might begin on the day following the management of the acute injuries at 500 micrograms once or twice daily for an indefinite period of time. There should be no adverse effects during the period required for recovery from the acute injury. Thus, the medication could be given continuously for up to 6 to 12 months in order to hasten recovery.
- the injectable GRF could be combined with daily injections of short acting testosterone analog or long acting depo testosterone as necessary.
- the long acting variety will deliver testosterone to the circulation over a period of three or more weeks.
- GRF(1-44)-NH 2 When in the above example a naturally occurring growth hormone releasing factor GRF(1-44)-NH 2 is replaced with biologically active analogs thereof, substantially similar results are obtained.
- the biologically active analogs of GRF(1-44)-NH 2 which can be used in the treatment process of this example are the following: GRF(1-44)-OH, GRF(1-40)-OH, GRF(1-40)-NH 2 , GRF(1-32)-NH 2 , GRF(1-39)-NH 2 , GRF(1-40)-Phe-NH 2 , GRF(1-40)-Phe-OH, GRF(1-40)-Phe-Gin-NH 2 , GRF(1-29)-NH 2 , and GRF(1-27)-NH 2 .
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- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
Description
__________________________________________________________________________ SEQUENCE LISTING (1) GENERAL INFORMATION: (iii) NUMBER OF SEQUENCES: 8 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 44 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 GluSerAsnGlnGluArgGlyAlaArgAlaArgLeu 3540 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 GluSerAsnGlnGluArgGlyAla 3540 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 39 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 GluSerAsnGlnGluArgGly 35 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 32 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArg 2025 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMet 2025 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 41 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 GluSerAsnGlnGluArgGlyAlaPhe 3540 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: Not Relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: TyrAlaAspAlaIlePheThrAsnSerTyrArgLysValLeuGlyGln 151015 LeuSerAlaArgLysLeuLeuGlnAspIleMetSerArgGlnGlnGly 202530 GluSerAsnGlnGluArgGlyAlaPheGln 3540 __________________________________________________________________________
Claims (20)
Priority Applications (1)
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US08/410,353 US5700775A (en) | 1995-03-24 | 1995-03-24 | Method and treatment composition for decreasing patient time in catabolic state after traumatic injury |
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US08/410,353 US5700775A (en) | 1995-03-24 | 1995-03-24 | Method and treatment composition for decreasing patient time in catabolic state after traumatic injury |
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US5700775A true US5700775A (en) | 1997-12-23 |
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US08/410,353 Expired - Lifetime US5700775A (en) | 1995-03-24 | 1995-03-24 | Method and treatment composition for decreasing patient time in catabolic state after traumatic injury |
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Cited By (9)
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US9096684B2 (en) | 2011-10-18 | 2015-08-04 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
US9845287B2 (en) | 2012-11-01 | 2017-12-19 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
US9957299B2 (en) | 2010-08-13 | 2018-05-01 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
US10202431B2 (en) | 2007-01-31 | 2019-02-12 | Aileron Therapeutics, Inc. | Stabilized P53 peptides and uses thereof |
US10213477B2 (en) | 2012-02-15 | 2019-02-26 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
US10227380B2 (en) | 2012-02-15 | 2019-03-12 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
US10253067B2 (en) | 2015-03-20 | 2019-04-09 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
US10301351B2 (en) | 2007-03-28 | 2019-05-28 | President And Fellows Of Harvard College | Stitched polypeptides |
US10471120B2 (en) | 2014-09-24 | 2019-11-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
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US10202431B2 (en) | 2007-01-31 | 2019-02-12 | Aileron Therapeutics, Inc. | Stabilized P53 peptides and uses thereof |
US10301351B2 (en) | 2007-03-28 | 2019-05-28 | President And Fellows Of Harvard College | Stitched polypeptides |
US9957299B2 (en) | 2010-08-13 | 2018-05-01 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
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US10308699B2 (en) | 2011-10-18 | 2019-06-04 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
US10213477B2 (en) | 2012-02-15 | 2019-02-26 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
US10227380B2 (en) | 2012-02-15 | 2019-03-12 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
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US10669230B2 (en) | 2012-11-01 | 2020-06-02 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
US10471120B2 (en) | 2014-09-24 | 2019-11-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
US10253067B2 (en) | 2015-03-20 | 2019-04-09 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
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